Validation of the Mediation Effect Between Cross-Cultural Management and Employee Identification.
Corporate culture faces a variety of cross-cultural challenges across the globe. Every culture retains and maintains different norms and customs, which are totally unique and different from other cultures. Consequently, employees from different cultures often experience various cross-cultural issues and challenges while working in transnational organizations where employees are needed to understand how people from diverse cultures must work together. The study used mixed research methodology for meeting the paper goals. Both positivism and phenomenology look relevant in a sense that they individually and collectively satisfy the paper objectives. To test mediation and moderation, the authors have used various hypotheses through collecting the sample size of 600 out of 6000 employees working for an Asian group encompassing more than 200 companies. Moderation and mediation strategic management research methods were used with the American Industrial Group in Asia as the setup of the study. Hypotheses were tested on effects of new corporate culture-based learning on the perception of social norms, learning attitude, self-efficacy, and social values. Additional hypotheses were also tested on the effects of perception of social norms, learning attitude, self-efficacy, social values, and psychological control on change intention. Perceived social norms directly affect the willingness to change as they have been used as mediating variables. Therefore, social norms affect corporate norms. The paper shows how mediation and moderation are understood and applied through understanding the relationship between local culture and corporate culture. The findings reveal how local culture affects corporate culture. However, there are certain limitations of the study; this includes that the study scope has mostly focused on an Asian context, therefore, it may not be applicable to other continents.


Smart breeding approaches in post-genomics era for developing climate-resilient food crops.
Improving the crop traits is highly required for the development of superior crop varieties to deal with climate change and the associated abiotic and biotic stress challenges. Climate change-driven global warming can trigger higher insect pest pressures and plant diseases thus affecting crop production sternly. The traits controlling genes for stress or disease tolerance are economically imperative in crop plants. In this scenario, the extensive exploration of available wild, resistant or susceptible germplasms and unraveling the genetic diversity remains vital for breeding programs. The dawn of next-generation sequencing technologies and omics approaches has accelerated plant breeding by providing the genome sequences and transcriptomes of several plants. The availability of decoded plant genomes offers an opportunity at a glance to identify candidate genes, quantitative trait loci (QTLs), molecular markers, and genome-wide association studies that can potentially aid in high throughput marker-assisted breeding. In recent years genomics is coupled with marker-assisted breeding to unravel the mechanisms to harness better better crop yield and quality. In this review, we discuss the aspects of marker-assisted breeding and recent perspectives of breeding approaches in the era of genomics, bioinformatics, high-tech phonemics, genome editing, and new plant breeding technologies for crop improvement. In nutshell, the smart breeding toolkit in the post-genomics era can steadily help in developing climate-smart future food crops.


Skeletal microcirculatory responses to hyperdynamic Escherichia coli sepsis in unanesthetized rats.
To determine the microvascular site of vasodilation during hyperdynamic sepsis, we measured arteriolar and venular responses to live Escherichia coli bacteremia in the rat cremaster muscle by direct in vivo videomicroscopy. Our data indicate that cardiac output (by thermodilution) increased, systemic vascular resistance decreased, and a differential arteriolar response occurred, with constriction of large arterioles and dilation of small terminal arterioles. We conclude that dilation of small terminal arterioles in skeletal muscle could contribute to decreased systemic vascular resistance during hyperdynamic sepsis. This may be an appropriate response to increased oxygen demand or decreased tissue utilization of oxygen. Alternatively, small-arteriole dilation may be an inappropriate response and secondary to release of vasoactive inflammatory mediators. If the latter is true, there is a potential therapeutic role for selective manipulation of the tone of small terminal arterioles in hyperdynamic sepsis.


Pathophysiology and natural history of anorectal sequelae following radiation therapy for carcinoma of the prostate.
To characterize the prevalence, pathophysiology, and natural history of chronic radiation proctitis 5 years following radiation therapy (RT) for localized carcinoma of the prostate. Studies were performed in 34 patients (median age 68 years; range 54-79) previously randomly assigned to either 64 Gy in 32 fractions over 6.4 weeks or 55 Gy in 20 fractions over 4 weeks RT schedule using 2- and later 3-dimensional treatment technique for localized prostate carcinoma. Each patient underwent evaluations of (1) gastrointestinal (GI) symptoms (Modified Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales including effect on activities of daily living [ADLs]); (2) anorectal motor and sensory function (manometry and graded balloon distension); and (3) anal sphincteric morphology (endoanal ultrasound) before RT, at 1 month, and annually for 5 years after its completion. Total GI symptom scores increased after RT and remained above baseline levels at 5 years and were associated with reductions in (1) basal anal pressures, (2) responses to squeeze and increased intra-abdominal pressure, (3) rectal compliance and (4) rectal volumes of sensory perception. Anal sphincter morphology was unchanged. At 5 years, 44% and 21% of patients reported urgency of defecation and rectal bleeding, respectively, and 48% impairment of ADLs. GI symptom scores and parameters of anorectal function and anal sphincter morphology did not differ between the 2 RT schedules or treatment techniques. Five years after RT for prostate carcinoma, anorectal symptoms continue to have a significant impact on ADLs of almost 50% of patients. These symptoms are associated with anorectal dysfunction independent of the RT schedules or treatment techniques reported here.


The Living Tomorrow Project: how Philip Morris has used a Belgian tourist attraction to promote ventilation approaches to the control of second hand smoke.
To examine the involvement of Philip Morris in Living Tomorrow 2 and determine the rationale behind its involvement. Research was conducted through a web based search of internal tobacco industry documents made publicly available through litigation. For approximately 1,000,000 euros Philip Morris (now Altria) became a co-initiator of Living Tomorrow 2, a tourist complex in Belgium that aims to demonstrate how we will be living in the future. In addition to promoting the company and its grocery products, Philip Morris is using the complex and its website to promote ventilation as a means of accommodating smokers and non-smokers in the indoor environment. Particular emphasis was placed on the bar and restaurant areas. Despite the rationale for its involvement, Philip Morris fails to acknowledge its role as a cigarette manufacturer. As a form of corporate sponsorship Philip Morris thought its involvement could evade any European tobacco advertising ban. Philip Morris is using a tourist attraction to promote its views on control of second hand smoke (SHS) and accommodation of smokers and non-smokers in the indoor environment. However, ventilation does not deal with the health effects of SHS. Policymakers must be cognisant of the devious tactics the industry employs to promote its own agenda, especially in relation to indoor air quality and smoking in public places. Tobacco control legislation should be continually modified and strengthened in response to the changing activities of the tobacco industry as it strives to evade existing legislation and deter the advent of new legislation.


CAG expansion induces nucleolar stress in polyglutamine diseases.
The cell nucleus is a major site for polyglutamine (polyQ) toxicity, but the underlying mechanisms involved have yet been fully elucidated. Here, we report that mutant RNAs that carry an expanded CAG repeat (expanded CAG RNAs) induce apoptosis by activating the nucleolar stress pathway in both polyQ patients and transgenic animal disease models. We showed that expanded CAG RNAs interacted directly with nucleolin (NCL), a protein that regulates rRNA transcription. Such RNA-protein interaction deprived NCL of binding to upstream control element (UCE) of the rRNA promoter, which resulted in UCE DNA hypermethylation and subsequently perturbation of rRNA transcription. The down-regulation of rRNA transcription induced nucleolar stress and provoked apoptosis by promoting physical interaction between ribosomal proteins and MDM2. Consequently, p53 protein was found to be stabilized in cells and became concentrated in the mitochondria. Finally, we showed that mitochondrial p53 disrupted the interaction between the antiapoptotic protein, Bcl-xL, and the proapoptotic protein, Bak, which then caused cytochrome c release and caspase activation. Our work provides in vivo evidence that expanded CAG RNAs trigger nucleolar stress and induce apoptosis via p53 and describes a polyQ pathogenic mechanism that involves the nucleolus.


Expertise in performance assessment: assessors' perspectives.
The recent rise of interest among the medical education community in individual faculty making subjective judgments about medical trainee performance appears to be directly related to the introduction of notions of integrated competency-based education and assessment for learning. Although it is known that assessor expertise plays an important role in performance assessment, the roles played by different factors remain to be unraveled. We therefore conducted an exploratory study with the aim of building a preliminary model to gain a better understanding of assessor expertise. Using a grounded theory approach, we conducted seventeen semi-structured interviews with individual faculty members who differed in professional background and assessment experience. The interviews focused on participants' perceptions of how they arrived at judgments about student performance. The analysis resulted in three categories and three recurring themes within these categories: the categories assessor characteristics, assessors' perceptions of the assessment tasks, and the assessment context, and the themes perceived challenges, coping strategies, and personal development. Central to understanding the key processes in performance assessment appear to be the dynamic interrelatedness of the different factors and the developmental nature of the processes. The results are supported by literature from the field of expertise development and in line with findings from social cognition research. The conceptual framework has implications for faculty development and the design of programs of assessment.


Association between impulsivity and neural activation to alcohol cues in heavy drinkers.
This study examines associations between two measures of impulsivity and brain response to alcohol taste cues. Impulsivity is both a risk factor for and a consequence of alcohol use and misuse. Frontostriatal circuits are linked to both impulsivity and addiction-related behaviors, including response to alcohol cues. Non-treatment-seeking heavy drinkers (n = 55) completed (i) an fMRI alcohol taste cue-reactivity paradigm; (ii) the monetary choice questionnaire (MCQ), a measure of choice impulsivity where participants choose between smaller, sooner rewards and larger, delayed rewards; (iii) and the UPPS-P Impulsive Behavior Scale, a self-report measure assessing five impulsivity factors. General linear models identified associations between neural alcohol taste cue-reactivity and impulsivity, adjusting for age, gender, and smoking status. Self-reported sensation seeking was positively associated with alcohol taste cue-elicited activation in frontostriatal regions, such that individuals who reported higher sensation seeking displayed greater neural response to alcohol taste cues. Conversely, delay discounting was negatively associated with activation in frontoparietal regions, such that individuals who reported greater discounting showed less cue-elicited activation. There were no significant associations between other self-reported impulsivity subscales and alcohol taste cue-reactivity. These results indicate that sensation seeking is associated with reward responsivity, while delay discounting is associated with recruitment of self-control circuitry.


Characterization of foliar manganese (Mn) in Mn (hyper)accumulators using X-ray absorption spectroscopy.
Plant hyperaccumulation of the essential nutrient manganese (Mn) is a rare phenomenon most evident in the Western Pacific region, and differs from hyperaccumulation of other elements. Mn hyperaccumulators employ a variety of species-dependent spatial distribution patterns in sequestering excess foliar Mn, including primary sequestration in both nonphotosynthetic and photosynthetic tissues. This investigation employed synchrotron X-ray absorption spectroscopy (XAS) in a comparative study of Mn (hyper)accumulators, to elucidate in situ the chemical form(s) of foliar Mn in seven woody species from Australia, New Caledonia and Japan. Foliar Mn was found to predominate as Mn(II) in all samples, with strong evidence of the role of carboxylic acids, such as malate or citrate, as complexing ligands. Overall, the X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine-structure spectroscopy (EXAFS) data appeared weighted against previous observations that oxalate binds excess Mn in Mn-(hyper)accumulating species.


How polymorphic markers contribute to genetic diseases in different populations? The study of inhibin A for premature ovarian insufficiency.
To verify the incidence of the G679A mutation in exon 2 of the gene inhibin alpha (INHA), in women with secondary amenorrhea and diagnosis of premature ovarian insufficiency, and in controls. A 5mL sample of peripheral blood was collected from all study participants in an EDTA tube and was used for DNA extraction. For the patient group, 5mL of blood were also collected in a tube containing heparin for karyotype, and 5mL were collected in a dry tube for follicle stimulant hormone dosage. All patient and control samples were initially submitted to analysis of the G679A variant in exon 2 of the INHA gene by PCR-RFLP technique. Samples from patients with premature ovarian insufficiency after PCR-RFLP were submitted to Sanger sequencing of the encoding exons 2 and 3. Sequencing was performed on ABI 3500 GeneticAnalyzer equipment and the results were evaluated by SeqA and Variant Reporter software. Samples of 70 women with premature ovarian insufficiency and 97 fertile controls were evaluated. The G769A variant was found in only one patient in the Premature Ovarian Insufficiency Group and in no control, and it appears to be rare in Brazilian patients with premature ovarian insufficiency. This polymorphism was previously associated to premature ovarian insufficiency in several populations worldwide. There is genetic heterogeneity regarding the INHA gene in different populations, and among the causes of premature ovarian insufficiency.


Effects of the small molecule HERG activator NS1643 on Kv11.3 channels.
NS1643 is one of the small molecule HERG (Kv11.1) channel activators and has also been found to increase erg2 (Kv11.2) currents. We now investigated whether NS1643 is also able to act as an activator of Kv11.3 (erg3) channels expressed in CHO cells. Activation of rat Kv11.3 current occurred in a dose-dependent manner and maximal current increasing effects were obtained with 10 µM NS1643. At this concentration, steady-state outward current increased by about 80% and the current increase was associated with a significant shift in the voltage dependence of activation to more negative potentials by about 15 mV. In addition, activation kinetics were accelerated, whereas deactivation was slowed. There was no significant effect on the kinetics of inactivation and recovery from inactivation. The strong current-activating agonistic effect of NS1643 did not result from a shift in the voltage dependence of Kv11.3 channel inactivation and was independent from external Na(+) or Ca(2+). At the higher concentration of 20 µM, NS1643 induced clearly less current increase. The left shift in the voltage dependence of activation reversed and the voltage sensitivity of activation dramatically decreased along with a slowing of Kv11.3 channel activation. These data show that, in comparison to other Kv11 family members, NS1643 exerts distinct effects on Kv11.3 channels with especially pronounced partial antagonistic effects at higher concentration.


Modeling peripheral olfactory coding in Drosophila larvae.
The Drosophila larva possesses just 21 unique and identifiable pairs of olfactory sensory neurons (OSNs), enabling investigation of the contribution of individual OSN classes to the peripheral olfactory code. We combined electrophysiological and computational modeling to explore the nature of the peripheral olfactory code in situ. We recorded firing responses of 19/21 OSNs to a panel of 19 odors. This was achieved by creating larvae expressing just one functioning class of odorant receptor, and hence OSN. Odor response profiles of each OSN class were highly specific and unique. However many OSN-odor pairs yielded variable responses, some of which were statistically indistinguishable from background activity. We used these electrophysiological data, incorporating both responses and spontaneous firing activity, to develop a bayesian decoding model of olfactory processing. The model was able to accurately predict odor identity from raw OSN responses; prediction accuracy ranged from 12%-77% (mean for all odors 45.2%) but was always significantly above chance (5.6%). However, there was no correlation between prediction accuracy for a given odor and the strength of responses of wild-type larvae to the same odor in a behavioral assay. We also used the model to predict the ability of the code to discriminate between pairs of odors. Some of these predictions were supported in a behavioral discrimination (masking) assay but others were not. We conclude that our model of the peripheral code represents basic features of odor detection and discrimination, yielding insights into the information available to higher processing structures in the brain.


Beliefs about promoting cognitive health among Filipino Americans who care for persons with dementia.
We examined beliefs about promoting cognitive health among Filipino Americans who care for persons with dementia, their awareness of media information about cognitive health, and their suggestions for communicating such information to other caregivers. We conducted three focus groups (25 participants). The constant comparison method compared themes across focus groups. Caregivers most frequently described cognitive health benefits of social engagement and leisure; next in emphasis were benefits of healthy diets. There was less emphasis on physical activity. Participants had heard from television that avoiding smoking, alcohol, and drugs might promote cognitive health. Ways to inform others about cognitive health included information in Filipino newspapers, and handouts in Filipino languages, distributed in Filipino stores, workplaces, community organizations, and health care facilities. Findings suggest an opportunity to develop public health messages promoting cognitive health that are in-language, published in ethnic-specific media, and that are culturally appropriate for Filipino and other Asian Americans.


Glycemic control in the ICU: a multicenter survey.
Intensive insulin therapy has recently been shown to decrease morbidity and mortality in the critically ill population in a large randomized clinical trial. To determine the beliefs and attitudes of ICU clinicians about glycemic control. Self-administered survey. ICU nurses and physicians in five university-affiliated multidisciplinary ICUs. A total of 317 questionnaires were returned from 233 ICU nurses and 84 physicians. The reported clinically important threshold for hypoglycemia was 4 mmol/l (median, IQR 3-4 mmol/l). In non-diabetic patients, the clinically important threshold for hyperglycemia was 10 mmol/l (IQR 9-12 mmol/l); however, nurses had a significantly higher threshold than physicians (difference of 0.52 mmol/l (95% CI 0.09-0.94 mmol/l, P=0.018). In diabetic patients, the clinically important threshold for hyperglycemia was also 10 mmol/l (IQR 10-12 mmol/l), and again nurses had a significantly higher threshold than physicians (0.81 mmol/l, 95% CI 0.29-1.32 mmol/l, P=0.0023). Avoidance of hyperglycemia was judged most important for diabetic patients (87.7%, 95% CI 84.1-91.3%), patients with acute brain injury (84.5%, 95% CI 80.5-88.5%), patients with a recent seizure (74.4%, 95% CI 69.6-79.3%), patients with advanced liver disease (64.0%, 95% CI 58.7-69.3%), and for patients with acute myocardial infarction (64.0%, 95% CI 58.7-69.3%). Physicians expressed more concern than nurses about avoiding hyperglycemia in patients with acute myocardial infarction ( P=0.0004). ICU clinicians raised concerns about the accuracy of glucometer measurements in critically ill patients (46.1%, 95% CI 40.5-51.6%). Attention to these beliefs and attitudes could enhance the success of future clinical, educational and research efforts to modify clinician behavior and achieve better glycemic control in the ICU setting.


Investigation of prevalence of dental anomalies by using digital panoramic radiographs.
This study was performed to evaluate the prevalence of all types and subtypes of dental anomalies among 6- to 40-year-old patients by using panoramic radiographs. This cross-sectional study was conducted by analysing digital panoramic radiographs of 1200 patients admitted to our clinic in 2014. Dental anomalies were examined under 5 types and 16 subtypes. Dental ano-malies were divided into 5 types: (a) number (including hypodontia, oligodontia and hyperdontia); (b) size (including microdontia and macrodontia); (c) structure (including amelogenesis imperfecta, dentinogenesis imperfecta and dentin dys-plasia); (d) position (including transposition, ectopia, displacement, impaction and inversion); (e) shape (including fusion-gemination, dilaceration and taurodontism). The prevalence of dental anomalies diagnosed by panoramic radiographs was 39.2% (46% in men and 54% in women). Anomalies of position (60.8%) and shape (27.8%) were the most common types of abnormalities and anomalies of size (8.2%), structure (0.2%) and number (17%) were the least in both genders. Anomalies of impaction (45.5%), dilacerations (16.3%), hypodontia (13.8%) and taurodontism (11.2%) were the most common subtypes of dental anomalies. Taurodontism was more common in the age groups of 13-19 years. The age range of the most frequent of all other anomalies was 20-29. Anomalies of tooth position were the most common type of dental anomalies and structure anomalies were the least common in this Turkish po-pulation. The frequency and type of dental anomalies vary within and between populations, confirming the role of racial factors in the prevalence of dental ano-malies. Digital panoramic radiography is a very useful method for the detection of dental anomalies. (Folia Morphol 2018; 77, 2: 323-328).


Three-dimensional coherence imaging in the Fresnel domain.
We show that three-dimensional incoherent primary sources can be reconstructed from finite-aperture Fresnel-zone mutual intensity measurements by means of coordinate and Fourier transformation. The spatial bandpass and impulse response for three-dimensional imaging that result from use of this approach are derived. The transverse and longitudinal resolutions are evaluated as functions of aperture size and source distance. The longitudinal resolution of three-dimensional coherence imaging falls inversely with the square of the source distance in both the Fresnel and Fraunhofer zones. We experimentally measure the three-dimensional point-spread function by using a rotational shear interferometer.


[Transplant Candidate with Cancer: Should We Proceed?]
Individuals who suffer from end-stage renal disease are at a higher risk of developing certain types of tumors. This risk increases as kidney function deteriorates further. Dialysis patients often witness a surge in the incidence of such malignancies. Interestingly, after the initial period following a kidney transplant, there is a dip in the number of deaths related to neoplasms. However, a long-term view reveals a progressive increase in the risk of developing tumors. The evaluation process for transplant candidacy is thorough, taking into account several factors, including the individual's history of neoplasms and the implications of immunosuppressive therapy. Immunosuppressive therapy is a double-edged tool in managing post-transplant complications, as it can foster environments conducive to neoplasm growth. It is essential to reevaluate, with the aid of an oncological opinion, the waiting time between cancer recovery and the listing for kidney transplantation, based on clinical data and follow-up. Independent of the type of tumor, the requirement to treat and achieve remission delays the listing process, consequently extending the time spent with end-stage renal disease and undergoing dialysis. These factors correlate with increased mortality, heightened risk of cardiovascular disease, and graft loss.


Role of viral ribonucleotide reductase in the increase of dTTP pool size in herpes simplex virus-infected Vero cells.
Infection of Vero cells with herpes simplex virus (HSV) causes a marked increase in the dTTP pool size of infected cells. In this study we examined the relative importance of the HSV-encoded ribonucleotide reductase (RR) and thymidine kinase (TK) in the increase of dTTP. In cells infected with an RR deletion mutant of HSV-1 strain KOS, there was no significant increase in the size of the dTTP pool, whereas the dTTP pool in HSV-1(TK-)-infected cells was increased in size to almost the same extent as that in HSV-1(TK+)-infected cells. Moreover, it was found that the increase in dTTP pool size was strongly inhibited by the addition of hydroxyurea, a specific inhibitor of RR, and 5-fluoro-2'-deoxyuridine, a specific inhibitor of thymidylate synthetase. These results suggest that the induction of viral RR is of primary importance in the increase of dTTP pool size in HSV-1-infected Vero cells.


Mobility restrictions and alcohol use during lockdown: "A still and dry pandemic for the many"?
Unexpected mobility disruptions during lockdown during the first wave of COVID-19 became 'tipping points' with the potential to alter pre-pandemic routines sensitive to socialisation. This paper investigates the impact of lockdown exposure on alcohol consumption. We document two findings using information from the Google Mobility Report and longitudinal data from the Understanding Society survey (UKHLS) in the United Kingdom. First, we find a sharp reduction in both actual mobility and alcohol use (consistent with a "still and dry pandemic for the many" hypothesis). However, we document an increase in alcohol use among heavy drinkers, implying a split behavioural response to COVID-19 mobility restrictions based on alcohol use prior to the pandemic. Second, using the predictions of the prevalence-response elasticity theory, we find that the pandemic's reduction in social contacts is responsible for a 2.8 percentage point reduction in drinking among men.


Lateral trochlear inclination measured by the transepicondylar axis holds potential for evaluating trochlear dysplasia in patients with lateral patellar dislocation.
To verify that lateral trochlear inclination (LTI) measured by the transepicondylar axis can reliably be used to evaluate trochlear dysplasia (TD) on MRI and can serve as an objective indication of trochleoplasty for patients with lateral patellar dislocation (LPD). Eighty patients with recurrent LPD and eighty healthy subjects were included. TD, posterior condylar angle (PCA), and LTI measured by the posterior condylar reference line (LTIp), surgical transepicondylar axis (LTIs), and anatomical transepicondylar axis (LTIa) were assessed on MRI. The intraclass correlation coefficient (ICC) and Bland-Altman analysis were performed, the correlations and differences amongst the parameters were identified, and a binary logistic regression model was established. Each measurement had excellent inter- and intra-observer agreement. The LTIp, LTIs and LTIa were smaller in the study group than in the control group, with mean differences of 9.0°, 7.2° and 7.0°, respectively (P < 0.001). The PCA was larger in patients with LPD than in the control group (P < 0.001). LTIp was associated with PCA in the study group (r = - 0.41, P < 0.001). The pathological values of LTIp, LTIs and LTIa were 11.7°, 15.3° and 17.4°, respectively. LTIs and LTIa were independent risk factors for LPD, with ORs of 7.33 (95% CI [1.06-52.90], P = 0.048) and 10.29 (95% CI [1.38-76.96], P = 0.023), respectively. The LTI can be reliably measured by MRI, but LTIp could potentially decrease the recorded value from the actual inclination angle. LTIs and LTIa are more appropriate to serve as trochleoplasty indications for patients with LPD, which could help orthopedists with surgical decision-making. Level III.


Epidemiology, etiology, diagnostic evaluation, and treatment of low back pain.
Low back pain affects a minority of individuals over 65 years of age. Four years after the onset of sciatica, the number of individuals working is independent of their workers' compensation status. A complex interaction of metalloproteinases, cytokines, chondrocytes, and macrophages are necessary for the resorption of herniated intervertebral discs. Positional magnetic resonance imaging in the seated extended posture identifies foraminal narrowing that is not visualized with conventional magnetic resonance studies. Compression associated with cauda equina syndrome must be reversed within 48 hours to preserve neurologic function. The gene for transforming growth factor can be transferred to intervertebral discs, resulting in increased proteogylcan production in a rabbit animal model. An aerobic exercise program is as effective as more expensive exercise programs in the treatment of chronic low back pain. Complementary therapies, willow bark and magnets, have marginal benefit for low back pain. Surgical intervention results in improved function for spinal stenosis patients.


Planning for sustainable cities by estimating building occupancy with mobile phones.
Accurate occupancy is crucial for planning for sustainable buildings. Using massive, passively-collected mobile phone data, we introduce a novel framework to estimate building occupancy at unprecedented scale. We show that, at urban-scale, occupancy differs widely from current estimates based on building types. For commercial buildings, we find typical occupancy rates are 5 times lower than current assumptions imply, while for residential buildings occupancy rates vary widely by neighborhood. Our mobile phone based occupancy estimates are integrated with a state-of-the-art urban building energy model to understand their impact on energy use predictions. Depending on the assumed relationship between occupancy and internal building loads, we find energy consumption which differs by +1% to -15% for residential buildings and by -4% to -21% for commercial buildings, compared to standard methods. This highlights a need for new occupancy-to-load models which can be applied at urban-scale to the diverse set of city building types.


Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: a phase I study.
The primary objective of this study was to evaluate the tolerability of single and multiple doses of abatacept in Japanese patients with rheumatoid arthritis. Secondary objectives included evaluating its pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy. This dose-escalation, single- and multiple-dose, multicenter, open-label study was conducted at nine sites in Japan. Seven patients were enrolled at each of three dose levels (2, 8 and 16 mg/kg) and received a single intravenous dose of abatacept on day 1 of the single-dose phase. The multiple-dose phase, at the same dose, started once the patients had completed the single-dose phase and when it was confirmed that there were no safety issues. Twenty patients started the single-dose phase. Single and multiple doses of abatacept were well tolerated, and adverse events were of mild to moderate intensity. There were no discontinuations or deaths due to adverse events. The pharmacokinetics of abatacept were linear, with no notable accumulation. There were no immunogenic effects on the safety, efficacy, or pharmacokinetics of abatacept. Multiple doses of abatacept improved individual items of the American College of Rheumatology core set. Single and multiple doses of abatacept showed favorable tolerability and efficacy in Japanese patients with rheumatoid arthritis.


Socioeconomic variations in the use of common surgical operations.
The surgical experience of a sample of people aged 40-64 randomly selected from general practice lists was elicited by means of a postal questionnaire and the results examined in relation to two indicators of socioeconomic status. Eighty per cent of the sample had had one or more surgical operations and women had a higher mean number of operations than men. Those in the more advantaged groups had a higher mean number of operations than those in the less advantaged groups. This difference was, however, mainly accounted for by operations carried out in childhood before the establishment of the National Health Service and by private sector surgery.


Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.
Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.


Computerized Cognitive Training (CCT) versus Yoga Impact on 12 Month Post Intervention Cognitive Outcome in Individuals with Mild Cognitive Impairment.
There is currently limited and mixed evidence for the cognitive benefits of Computerized Cognitive Training (CCT) and yoga in persons with Mild Cognitive Impairment (pwMCI). The objective of this study was to investigate the benefit of computerized cognitive training (CCT) vs. physical (yoga) intervention on cognitive abilities. Participants in this study were part of the larger Mayo Clinic's Healthy Action to Benefit Independence and Thinking (HABIT) program comparative effectiveness trial. The HABIT program is designed for pwMCI and their care partner and consists of five behavioral interventions: CCT, Memory Support System-Calendar (MSS-Calendar), wellness education, support groups, and yoga. The subtractive study design randomly withheld one of the interventions for a total of five study arms. Longitudinal mixed-effects regression models were used to investigate the hypothesis that CCT and yoga has a greater positive impact on psychomotor and basic attention abilities at 12 months post-intervention as compared to the other HABIT interventions. Findings showed CCT had a positive impact compared to yoga on the Cogstate psychomotor/attention composite at 12 months post-intervention (ES = 0.54; unadjusted p value = 0.007, adjusted p value = 0.021). The impact of yoga or combining CCT with yoga did not show statistically significant improvement. Continued CCT practice at home showed further benefit on psychomotor/attention at 12 months post-intervention. There was no significant benefit of CCT or yoga on Cogstate learning/working memory composite.


Head-to-head comparison of 19 prediction models for short-term outcome in medical patients in the emergency department: a retrospective study.
Prediction models for identifying emergency department (ED) patients at high risk of poor outcome are often not externally validated. We aimed to perform a head-to-head comparison of the discriminatory performance of several prediction models in a large cohort of ED patients. In this retrospective study, we selected prediction models that aim to predict poor outcome and we included adult medical ED patients. Primary outcome was 31-day mortality, secondary outcomes were 1-day mortality, 7-day mortality, and a composite endpoint of 31-day mortality and admission to intensive care unit (ICU).The discriminatory performance of the prediction models was assessed using an area under the receiver operating characteristic curve (AUC). Finally, the prediction models with the highest performance to predict 31-day mortality were selected to further examine calibration and appropriate clinical cut-off points. We included 19 prediction models and applied these to 2185 ED patients. Thirty-one-day mortality was 10.6% (231 patients), 1-day mortality was 1.4%, 7-day mortality was 4.4%, and 331 patients (15.1%) met the composite endpoint. The RISE UP and COPE score showed similar and very good discriminatory performance for 31-day mortality (AUC 0.86), 1-day mortality (AUC 0.87), 7-day mortality (AUC 0.86) and for the composite endpoint (AUC 0.81). Both scores were well calibrated. Almost no patients with RISE UP and COPE scores below 5% had an adverse outcome, while those with scores above 20% were at high risk of adverse outcome. Some of the other prediction models (i.e. APACHE II, NEWS, WPSS, MEWS, EWS and SOFA) showed significantly higher discriminatory performance for 1-day and 7-day mortality than for 31-day mortality. Head-to-head validation of 19 prediction models in medical ED patients showed that the RISE UP and COPE score outperformed other models regarding 31-day mortality.


MicroRNA-488 regulates diabetic nephropathy via TGF-β1 pathway.
The aim of this study was to clarify the biological roles of microRNA-488 and transforming growth factor β1 (TGF-β1) pathway in the occurrence and progression of diabetic nephropathy (DN). Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expressions of microRNA-488, fibrinogen factors coII, coIIV, and fibronectin (FN) in Human mesangial cells (HMCs) with high-glucose or low-glucose treatment. After transfection of microRNA-488 mimics or inhibitor, expression levels of coII, coIIV, and FN in HMCs were determined by qRT-PCR and Western blot. Their expressions in HMC cells treated with different doses of TGF-β1 at different time points were also detected. Finally, we evaluated the potential influence of microRNA-488 on TGF-β1-induced fibrosis of HMC cells by qRT-PCR. Compared with low-glucose treatment, the expression of microRNA-488 markedly increased in HMCs treated with high-glucose, as well as coII, coIIV, and FN. Overexpression of microRNA-488 remarkably upregulated mRNA and protein levels of coII, coIIV, and FN, whereas microRNA-488 knockdown downregulated their levels. Expression levels of microRNA-488, coII, coIIV, and FN gradually upregulated with the increase of TGF-β1 dose and treatment duration. MicroRNA-488 regulates the development of diabetic nephropathy-induced fibrosis by TGF-β1 pathway.


Evaluation of the microplate leukocyte adherence inhibition test and its reproducibility, sensitivity, and relationship to other tests of cellular immunity.
The microplate version of the leukocyte adherence inhibition (LAI) test was evaluated in murine and human studies. It was used in parallel with the microcytotoxicity assay, lymphotoxin assay, leukocyte migration inhibition, and lymphocyte stimulation tests in a transplantable murine tumor model, and it compared favorably with these established techniques for the detection of cellular immunity. The LAI test detected both primary and secondary anamnestic responses in Bacillus Calmette-Guérin-primed mice, and it displayed sensitivity to host humoral factors comparable to that seen with other tests. The LAI phenomenon was shown to be mediated by a soluble supernatant factor liberated by antigen-exposed immune leukocytes in the mouse and by concanavalin A-stimulated human leukocytes. In the mouse, deliberate depletion of T-cells ablates LAI reactivity in cells taken at the peak of a primary response; however, immune serum "arms" non-thymus-dependent cells taken from unimmunized hosts. In the mouse, the results of LAI tests correlate with other established techniques, when purified protein derivative reactivity was assessed in spleen cells from Bacillus Calmette-Guérin-immunized mice. Comparable correlation is not found when reactivity to this antigen is assessed in human peripheral blood samples from unimmunized donors.


Interaction of Aβ(1-42) amyloids with lipids promotes "off-pathway" oligomerization and membrane damage.
The toxicity of amyloids, as Aβ(1-42) involved in Alzheimer disease, is a subject under intense scrutiny. Many studies link their toxicity to the existence of various intermediate structures prior to fiber formation and/or their specific interaction with membranes. In this study we focused on the interaction between membrane models and Aβ(1-42) peptides and variants (L34T, mG37C) produced in E. coli and purified in monomeric form. We evaluated the interaction of a toxic stable oligomeric form (oG37C) with membranes as comparison. Using various biophysical techniques as fluorescence and plasmon waveguide resonance, we clearly established that the oG37C interacts strongly with membranes leading to its disruption. All the studied peptides destabilized liposomes and accumulated slowly on the membrane (rate constant 0.02 min(-1)). Only the oG37C exhibited a particular pattern of interaction, comprising two steps: the initial binding followed by membrane reorganization. Cryo-TEM was used to visualize the peptide effect on liposome morphologies. Both oG37C and mG37C lead to PG membrane fragmentation. The PG membrane promotes peptide oligomerization, implicated in membrane disruption. WT (Aβ(1-42)) also perturbs liposome organization with membrane deformation rather than disruption. For all the peptides studied, their interaction with the membranes changes their fibrillization process, with less fibers and more small aggregates being formed. These studies allowed to establish, a correlation between toxicity, fiber formation, and membrane disruption.


Preliminary Assessment of COVID-19 Implications for the Water and Sanitation Sector in Latin America and the Caribbean.
COVID-19 has had a severe impact on human health, as well as in social and economic terms, with implications for the management and governance of the water and sanitation sector. These implications are evident in Latin America and the Caribbean due to existing challenges the region faces in accessing water and sanitation services. In spite of significant advances, around 65 million people in the LAC region currently lack appropriate access to water and soap to wash their hands-one of the most basic measures to prevent the spread of disease. Furthermore, social and economic vulnerabilities have exacerbated the effects of the pandemic in the region, particularly among those living in poverty. The COVID-19 pandemic thus requires the mobilization of frameworks such as the human rights to water and sanitation, specifically considering the region's realities. This paper provides a review of some of the challenges currently faced in the region and advances a series of recommendations for enhancing access to water, sanitation and hygiene. The importance of effective governance, management and communication strategies in the water provisioning sector is highlighted in the context of the pandemic, and the role of science and research for adequate decision making is emphasized.


Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones.
The in vitro activity of the novel 8-methoxyquinolone, moxifloxacin, against Streptococcus pneumoniae was evaluated, and the intracellular targets of this agent were studied. Analysis of mutant strains selected with moxifloxacin demonstrated that first-step mutants bore amino acid substitutions at position 81 in the GyrA subunit of DNA gyrase. This suggests that, unlike older fluoroquinolone agents such as ciprofloxacin and levofloxacin, but similar to other C-8 substituted quinolones like sparfloxacin and gatifloxacin, moxifloxacin targets the GyrA subunit of DNA gyrase as an initial lethal event. Such a mechanism results in high activity against increasingly common S. pneumoniae strains bearing substitutions in DNA topoisomerase IV. Moxifloxacin was active with an MIC of </= 0.25 mg/L against S. pneumoniae clinical isolates, and against mutants, selected in the laboratory with ciprofloxacin or levofloxacin, that bore a Ser-79-->Phe/Tyr substitution in ParC. The moxifloxacin MIC for strains with mutations in the structural genes for both DNA gyrase subunit GyrA and DNA topoisomerase IV subunit ParC did not exceed 2 mg/L, a level within clinically achievable serum concentrations for this agent. We also found that moxifloxacin is a poor substrate for active efflux in S. pneumoniae. Therefore, the high activity of moxifloxacin against S. pneumoniae appears to be a result of both enhanced activity against DNA gyrase and topoisomerase IV, and reduced efflux from the bacterial cell.


The epidemiology of family meals among Ohio's adults.
The epidemiology of family meals among adults at a population level is poorly characterized and whether living with children impacts this health behaviour is uncertain. We determined the prevalence of family meals among US adults in a mid-western state whose families did and did not include minor children and described how it varied by sociodemographic characteristics. The cross-sectional 2012 Ohio Medicaid Assessment Survey is representative of Ohio adults and included questions on their sociodemographic characteristics and the frequency with which they eat family meals at home. Trained interviewers administered landline and cell phone surveys to adults sampled from Ohio's non-institutionalized population. We analysed data from 5766 adults living with minor children and 8291 adults not living alone or with children. The prevalence of family meals was similar for adults who did and did not live with minor children: 47 % (95 % CI 46, 49 %) of adults living with and 51 % (95 % CI 50, 53 %) of adults living without children reported eating family meals on most (six or seven) days of the week. Family meal frequency varied by race/ethnicity, marital and employment status in both groups. Non-Hispanic African-American adults, those who were not married and those who were employed ate family meals less often. Adults in Ohio frequently shared meals with their family and family meal frequency was not strongly related to living with children. Broadening the scope of future studies to include adults who are not parents could enhance our understanding of the potential health benefits of sharing meals.


Subtotal cholecystectomy for the hostile gallbladder: failure to control the cystic duct results in significant morbidity.
Outcomes following the inability to control the cystic duct due to a hostile triangle of Calot during cholecystectomy remain unknown. The purpose of this study was to analyze the safety and efficacy of subtotal cholecystectomy, with attention to the necessity for secondary interventions. Sixteen thousand five hundred ninety six cholecystectomies from January 2002 to August 2014 were reviewed, identifying patients managed with subtotal cholecystectomy, defined as the inability to isolate/transect the cystic duct. After propensity matching, we investigated surgical indications, perioperative outcomes, and the necessity for secondary ERCP, percutaneous drainage, and completion cholecystectomy. 65 (0.39%) patients underwent subtotal cholecystectomy; 54 (83.1%) began laparoscopically, of which 30 (55.6%) required conversion to laparotomy. Subtotal cholecystectomy, performed more frequently for acute cholecystitis (70.8% vs 34.6%), was associated with extended hospitalizations (4 d vs 2 d) and frequent surgical site infections (20% vs 4.6%). 25 (38.5%) subtotal cholecystectomy patients required ≥1 secondary intervention, and compared to standard cholecystectomy, underwent higher rates postoperative ERCP (30.8% vs 5.4%), percutaneous drainage (9.2% vs 1.5%), and completion cholecystectomy (6.2% vs 0%) [all P < 0.05]. Subtotal cholecystectomy fails to control the cystic duct, resulting in significant morbidity. Most do not require completion cholecystectomy; however, patients demand close observation and, frequently, secondary interventions.


Persistence mechanisms in Pseudomonas aeruginosa from cystic fibrosis patients undergoing ciprofloxacin therapy.
The mechanisms of persistence to ciprofloxacin in nine sets of Pseudomonas aeruginosa strains isolated during ciprofloxacin therapy of chronic lung infections in cystic fibrosis patients were studied. Low to moderate levels of ciprofloxacin resistance developed in each case. Each set of pretherapy ciprofloxacin-susceptible, during-therapy ciprofloxacin-resistant, and posttherapy ciprofloxacin-susceptible isolates were shown to be genotypically related by using a radiolabeled epidemiological gene probe. All ciprofloxacin-resistant isolates were found to have altered susceptibilities to both nalidixic acid and various chemically unrelated antibiotics. Analysis of possible resistance mechanisms showed that the strains had altered outer membrane protein or lipopolysaccharide profiles. Complementation of possible DNA gyrase mutations with a plasmid-borne, wild-type Escherichia coli gyrA gene indicated that altered DNA gyrase was at least partly responsible for ciprofloxacin resistance in all strains tested. Attempts to generate ciprofloxacin-susceptible revertants in vitro showed that in some strains reversion was rapid in the absence of ciprofloxacin, while in other strains it was not possible to generate revertants. These data indicate that persistence of Pseudomonas aeruginosa to ciprofloxacin involves changes in DNA gyrase and is associated with pleiotropic changes in outer membrane proteins and lipopolysaccharide.


α-Mangostin from Cratoxylum arborescens demonstrates apoptogenesis in MCF-7 with regulation of NF-κB and Hsp70 protein modulation in vitro, and tumor reduction in vivo.
Cratoxylum arborescens is an equatorial plant belonging to the family Guttiferae. In the current study, α-Mangostin (AM) was isolated and its cell death mechanism was studied. HCS was undertaken to detect the nuclear condensation, mitochondrial membrane potential, cell permeability, and the release of cytochrome c. An investigation for reactive oxygen species formation was conducted using fluorescent analysis. To determine the mechanism of cell death, human apoptosis proteome profiler assay was conducted. In addition, using immunofluorescence and immunoblotting, the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma (Bcl)-2 proteins were also tested. Caspaces such as 3/7, 8, and 9 were assessed during treatment. Using HCS and Western blot, the contribution of nuclear factor kappa-B (NF-κB) was investigated. AM had showed a selective cytotoxicity toward the cancer cells with no toxicity toward the normal cells even at 30 μg/mL, thereby indicating that AM has the attributes to induce cell death in tumor cells. The treatment of MCF-7 cells with AM prompted apoptosis with cell death-transducing signals. This regulated the mitochondrial membrane potential by down-regulation of Bcl-2 and up-regulation of Bax, thereby causing the release of cytochrome c from the mitochondria into the cytosol. The liberation of cytochrome c activated caspace-9, which, in turn, activated the downstream executioner caspace-3/7 with the cleaved poly (ADP-ribose) polymerase protein, thereby leading to apoptotic alterations. Increase of caspace 8 had showed the involvement of an extrinsic pathway. This type of apoptosis was suggested to occur through both extrinsic and intrinsic pathways and prevention of translocation of NF-κB from the cytoplasm to the nucleus. Our results revealed AM prompt apoptosis of MCF-7 cells through NF-κB, Bax/Bcl-2 and heat shock protein 70 modulation with the contribution of caspaces. Moreover, ingestion of AM at (30 and 60 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that AM is a potentially useful agent for the treatment of breast cancer.


Viral etiology of influenza-like illnesses during the influenza season between December 2011 and April 2012.
The aim of this study was to determine the frequency of respiratory viruses responsible for respiratory tract infections in Turkish children during the 2011-2012 influenza season. Nasal swabs were obtained from patients with symptoms suggestive of an influenza-like illness between December 2011 and April 2012. Samples were analyzed with multiplex real-time polymerase chain reaction (RT-PCR) to help identify the causative viral pathogen. A total of 200 patients were enrolled in the study. A respiratory virus was detected successfully in 102 (51%) children; influenza A (H3N2) in 39.2%, influenza B in 23.5%, RSV in 15.6%, rhinovirus in 13.7%, bocavirus in 2.9%, coronavirus in 2.9%, and metapneumovirus in 0.9% of patients. Only one patient was co-infected with bocavirus and influenza A virus. A statistically significant difference in the mean age of presentation was observed between the various viral pathogens (P < 0.001). Patients with RSV were significantly younger whereas children infected with the influenza viruses were significantly older. Comparison of symptoms revealed that fever and headache occurred more frequently with the influenza viruses than the other viruses combined (P < 0.001, <0.05). Durations of symptoms such as fever, cough, nasal congestion, and rhinorrhea were also significantly longer in the influenza group (P < 0.001, <0.005, <0.001, <0.005, respectively). Demographic analyses revealed that the school/daycare attendance was the only parameter associated with a significantly increased risk for influenza infection. With an overall viral pathogen detection rate of 51%, findings of the present study suggest other respiratory pathogens, whether viral or bacterial, may also lead to hospital visits due to influenza-like illnesses in children.


Identification of an alcoholic beverage in which methamphetamine was dissolved.
A man was arrested for violating the Stimulant Control Law. Twelve small plastic containers each containing 1-3 ml of reddish purple alcoholic beverage in which methamphetamine had been dissolved, and a bottle of blueberry liquor of a similar colour, were found in his house. He admitted that the blueberry liquor belonged to him, but strongly insisted that he had been asked to keep the containers by another person and that he had no knowledge of their contents. The alcoholic beverage and the blueberry liquor were analyzed in order to test whether he had dissolved methamphetamine in the blueberry liquor. The aroma components found in the alcoholic beverage in each of the plastic containers were identical, but differed from those found in the blueberry liquor. Based on these results and further police investigations, the suspect's allegation was supported and he was not prosecuted.


[Managing a high risk pregnancy after liver transplantation from the obstetrician's point of view. A case report].
We report about a pregnancy and obstetrical management of a patient who had undergone a liver transplantation. Following a normal pregnancy, the newborn was born spontaneously in the 39th week of pregnancy. During the pregnancy the CSA blood levels were controlled frequently as well as the fetal development. An amniocentesis for chromosomal analysis, measurement of AFP blood levels, virus diagnostic and a phase III ultrasound diagnostic were performed. Immediately after delivery the baby was examined carefully by a pediatrician. Management of such a risk pregnancy, after organ transplantation, is possible if there is a close interdisciplinary cooperation between obstetricians, pediatricians, transplant surgeons and internal medicine specialist.


Generation of a potent chimeric toxin by replacement of domain III of Pseudomonas exotoxin with ricin A chain KDEL.
Following cellular uptake, Pseudomonas exotoxin (PE) is cleaved by cellular protease which generates an enzymatically active C-terminal fragment (amino acids 280-613). This 37 kD fragment translocates to the cell cytosol where it ADP-ribosylates elongation factor 2 and inhibits protein synthesis. A recombinant hybrid toxin (designated PE-RTA) in which the ADP-ribosylation domain (domain 111) was replaced by the RNA N-glycosidase domain of ricin (the A chain or RTA) has been produced in E. coli. The hybrid toxin effectively and specifically depurinated 28S ribosomal RNA, indicating that the ricin A moiety folded into its native conformation. The cytotoxicity of PE-RTA for L929 cells was approximately 100-fold less than either native PE or whole ricin. However, the addition of the tetrapeptide KDEL to the C-terminus of PE-RTA (producing PE-RTA KDEL) increased cytotoxicity to the level of the native toxins. By analogy to PE, both PE-RTA and PE-RTA KDEL would be proteolytically cleaved within PE domain II during cell entry. A single amino acid substitution, believed to disrupt an essential step in the transport of the catalytically active PE fragment to the cell cytosol (Trp281 to Ala: Zdanovsky, A.G., Chiron, M., Pastan, I., and FitzGerald, D. J. (1993) J. Biol. Chem. 268, 21791-21799), reduced the cytotoxicities of both PE and PE-RTA KDEL by approximately 100-fold. Taken together, these data show that the ricin A chain component of the hybrid toxin requires essential PE-derived sequences at both the N- and C-termini of the translocating fragment. Clearly, in the context of this fusion protein, ricin A chain cannot effect its own transfer to the cytosol.


Carbon emission potential of new energy vehicles under different electricity structures.
New energy vehicles have a significant impact on reducing green house gas (GHG) emissions in the transportation sector, but the ability of new energy vehicles to reduce emissions under various development scenarios and electricity energy mix needs to be studied in depth. In this research, a GRA-BiLSTM model is constructed to predict the ownership of new energy vehicles by three scenario settings. Then, the structure of the future energy generation is forecast using a regression model. Finally, the carbon emissions under different energy structures are quantified and compared based on the prediction results, focusing on their carbon emission effects. The results show that in 2035, under three different development scenarios, the new energy vehicle ownership will reach 5711, 18122.76, and 218.93 million units, and the carbon emissions will be 60.897 billion kg, 193.246 billion kg, and 233.451 billion kg, respectively, based on the future energy development structure, accounting for 86% of the carbon emissions from the existing power generation structure. The carbon emission potential of new energy vehicles depends to a large extent on the future scenario of the power generation mix as well as the market for new energy vehicle ownership.


Association Between Catheter Ablation and Dementia Among Patients With Atrial Fibrillation: A Systematic Review and Meta-analysis.
Atrial fibrillation (AF) is associated with an increased risk of Dementia. However, the association between catheter ablation (CA) in patients with atrial fibrillation and the risk of dementia is not well established, with conflicting results to date. We aimed to evaluate the association between CA patients and the risk of Dementia. We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until 10th May 2023. Hazard ratios (HR) were pooled using a random-effect model, and a P-value of < 0.05 was considered statistically significant. A total of 5 studies with 125,649 patients (30,192 in the CA group and 95,457 in the non-CA group) were included. The mean age of patients among CA and non-CA groups was comparable (58.7 vs 58.18). The most common comorbidity among CA and non-CA groups was hypertension (18.49% vs 81.51%), respectively. Pooled analysis of primary outcome showed that CA was associated with a significant reduction in the risk of Dementia (HR, 0.63 [95% CI: 0.52-0.77], P < 0.001). Similarly, pooled analysis of secondary outcomes showed that the patients with CA had a lower risk of Alzheimer's disease (HR, 0.78 [95% CI: 0.66-0.92], P < 0.001) compared with the non-CA group. However, there was no statistically significant difference in the risk of vascular dementia (HR, 0.63 [95% CI: 0.38-1.06], P = 0.08) between both groups of patients. Our study suggested that catheter ablation reduced the risk of dementia and Alzheimer's disease compared to the nonablation group of patients.


Psychometric Properties of a Spanish Version of the Fear of COVID-19 Scale in General Population of Lima, Peru.
The current pandemic of the novel coronavirus COVID-19 has increased the anxiety and fear experienced by many. The main objective of this study was to analyze the psychometric properties of the Spanish-translated version of the Fear of COVID-19 Scale (FCV-19S) using a sample of population in Peru. This is a cross-sectional instrumental study. Data were collected by a convenience sampling method, resulting in a total of 832 participants, and the collection took place over 1 week, April 17-23, 2020. The original version of the FCV-19S was translated from English into Spanish. The results support a bifactor model consisting of one general factor and two specific factors-one of emotional fear reactions and another of somatic expressions of fear of COVID-19 (CFI = 0.988, RMSEA = 0.075). Invariance between healthcare workers and age groups was reached (ΔCFI < 0.01), but the invariance between men and women was not met (ΔCFI = 0.02). Convergent validity was found with depressive, anxious, and posttraumatic stress symptoms. The general factor of the fear of COVID-19 and two specific factors had an optimal level of internal consistency (ω > 0.89 and α > 0.83). The study found the Spanish-translated version of the FCV-19S has good psychometric properties and presents evidence of validity and reliability.


Seroprevalence of chronic Chlamydia pneumoniae infection in patients affected by chronic stable asthma.
To evaluate the seroprevalence of Chlamydia pneumoniae and age, gender and smoking habits in stable asthmatic patients. Over a period of 3 months, 197 adult patients affected by intermittent-to-severe chronic asthma were enrolled from 16 respiratory disease units in the south of Italy. As a control group, we tested 185 healthy, non-asthmatic subjects matched for age and gender, recruited among hospital staff. All patients were submitted to clinical examination, spirometry and blood collection for C. pneumoniae serology. The presence of infection was investigated by microimmunofluorescence (Micro-IF Test) for C. pneumoniae-specific IgG, IgM and IgA antibodies. C. pneumoniae IgG titers > or =1 : 64 were detected in 30.4% of asthmatics and in 30.8% of controls. Correlation of age, gender and smoking habit with C. pneumoniae seropositivity was evaluated by linear regression analysis. Age was significantly associated with C. pneumoniae IgG titer > or =1 : 64 when seropositive asthmatics were tested. Moreover, C. pneumoniae seroprevalence was higher among smokers with a diagnosis of chronic asthma. The seroprevalence of C. pneumoniae in stable asthmatics was comparable with the controls; therefore, the study does not support the association between C. pneumoniae antibody titers and stable asthma. However, the analysis for likely confounders such as age, gender and smoking status suggests a possible association of enhanced susceptibility to C. pneumoniae infection with age and smoking habitus.


[Localization by bone SPET of osteoid osteoma in the vertebral lamina].
The combined use of bone SPET and CT was a good approach for diagnosing an osteoid osteoma of spine in a 16-year-old young woman with a history of several months of back pain. Pain was increased at night and relieved by aspirin intake. Plain films of the spine only revealed a scoliosis. Bone SPET demonstrated a focal increased activity in the left posterior elements of T12 vertebra. CT of this vertebra discovered a lytic lesion in the left lamina. An osteoid osteoma was removed by laminectomy.


UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase.
The incidence of hypertension and cardiovascular disease (CVD) correlates with latitude and rises in winter. The molecular basis for this remains obscure. As nitric oxide (NO) metabolites are abundant in human skin, we hypothesized that exposure to UVA may mobilize NO bioactivity into the circulation to exert beneficial cardiovascular effects independently of vitamin D. In 24 healthy volunteers, irradiation of the skin with two standard erythemal doses of UVA lowered blood pressure (BP), with concomitant decreases in circulating nitrate and rises in nitrite concentrations. Unexpectedly, acute dietary intervention aimed at modulating systemic nitrate availability had no effect on UV-induced hemodynamic changes, indicating that cardiovascular effects were not mediated via direct utilization of circulating nitrate. UVA irradiation of the forearm caused increased blood flow independently of NO synthase (NOS) activity, suggesting involvement of pre-formed cutaneous NO stores. Confocal fluorescence microscopy studies of human skin pre-labeled with the NO-imaging probe diaminofluorescein 2 diacetate revealed that UVA-induced NO release occurs in a NOS-independent, dose-dependent manner, with the majority of the light-sensitive NO pool in the upper epidermis. Collectively, our data provide mechanistic insights into an important function of the skin in modulating systemic NO bioavailability, which may account for the latitudinal and seasonal variations of BP and CVD.


New test hemisphere for evaluation and development of ablation profiles.
To develop and apply a new evaluation device for testing excimer laser ablation that allows a three-dimensional test of the characteristics of the imparted ablation. A specially designed PMMA hemisphere with a 43.00-D curvature was developed, and results obtained with different algorithms and profiles of curvature with the Nidek EC-5000 excimer laser were evaluated. Topography, OPD-scan, wavefront, and keratoscopy were performed before and after ablation. The test hemisphere proved to be a reliable tool, allowing repeatable ablation results, precise calibration results, as well as experimental evaluation and comparison of new profiles. This new PMMA hemisphere can be used to improve the understanding of commonly used ablation algorithms and profiles, as well as in the daily safety routine and the experimental development and evaluation of advanced treatment solutions in excimer laser refractive surgery.


MRI appearance of spinal lesions: metastatic tumors or infections?
Three patients with pathologically verified spinal osteomyelitis and another three with metastatic tumors of the spine were investigated. MRI of th spine of four patients showed several unusual findings. The preservation of intervertebral discs and endplates did not predict accurately the diagnosis of either infections or tumors. The "pepper and salt" appearing feature may also occur in a metastatic tumor. Plain radiographs, CT, and radioisotope bone scans were less sensitive than MRI to disclose the lesions. In cases of osteomyelitis, the systemic sources of infections were frequently not found, and the responsible microorganisms could not be identified even from the surgical specimens of two patients. However, mycobacterium tuberculosis was found in the surgical specimen of a patient with cervical spinal lesion whose MRI was indistinguishable from a metastatic tumor. Surgicopathological diagnosis was therefore crucial and mandatory in these instances.


Neodymium concentration measurements in Nd:YLF laser rods: a nondestructive method.
A nondestructive method for measurements of Nd(3+) concentration in Nd:YLF laser rodes is presented. The method, based on the comparison of the intensities of Nd(3+) luminescence lines to the intensities of the host matrix (LiYF(4)) Raman lines, requires the use of a micro-Raman spectrometer. The experimental conditions have been optimized and are described in detail. The investigations were performed in the concentration range 0at.%-2at.% of Nd and the calibration curve is presented. In standard use, the relative error on the results never exceeds 10%. Using this method to study the concentration gradient in a crystal is shown and the distribution coefficient of Nd(3+) in LiYF(4) is deduced.


The use of yank-time signal as an alternative to identify kinematic events and define phases in human countermovement jumping.
Detailed examinations of both the movement and muscle activation patterns used by animals and humans to complete complex tasks are difficult to obtain in many environments. Therefore, the ability to infer movement and muscle activation patterns after capture of a single set of easily obtained data is highly sought after. One possible solution to this problem is to capture force-time data through the use of appropriate transducers, then interrogate the signal's derivative, the yank-time signal, which amplifies, and thus highlights, temporal force-time changes. Because the countermovement vertical jump (CMJ) is a complex movement that has been well studied in humans, it provides an excellent preliminary model to test the validity of this solution. The aim of the present study was therefore to explore the use of yank-time signal, derived from vertical ground reaction force-time data, to identify and describe important kinematic (captured using three-dimensional motion analysis) and kinetic events in the CMJ, and to relate these to possible muscle activation (electromyography) events that underpin them. It was found that the yank-time signal could be used to accurately identify several key events during the CMJ that are likely to be missed or misidentified when only force-time data are inspected, including the first instances of joint flexion and centre of mass movement. Four different jump profiles (i.e. kinematic patterns) were inferred from the yank-time data, which were linked to different patterns of muscle activation. Therefore, yank-time signal interrogation provides a viable method of estimating kinematic patterns and muscle activation strategies in complex human movements.


Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors.
The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.


Croceicoccus naphthovorans sp. nov., a polycyclic aromatic hydrocarbons-degrading and acylhomoserine-lactone-producing bacterium isolated from marine biofilm, and emended description of the genus Croceicoccus.
A polycyclic aromatic hydrocarbons-degrading and acylhomoserine-lactone-producing marine bacterium, designated strain PQ-2(T), was isolated from marine biofilm collected from a boat shell at a harbour of Zhoushan island in Zhejiang Province, PR China. Strain PQ-2(T) is Gram-stain-negative, yellow-pigmented, non-motile and short rod-shaped. Optimal growth of strain PQ-2(T) was observed at 32 °C, at pH 7.0 and in 2% (w/v) NaCl. The 16S rRNA gene sequence of strain PQ-2(T) showed highest similarity to Croceicoccus marinus E4A9(T) (96.3%) followed by Novosphingobium malaysiense MUSC 273(T) (95.6%) and Altererythrobacter marinus H32(T) (95.6%). Phylogenetic analysis with all species of the family Erythrobacteraceae with validly published names revealed that strain PQ-2(T) formed a phyletic line with Croceicoccus marinus E4A9(T) that was distinct from other members of the family Erythrobacteraceae . The sole respiratory quinone was ubiquinone 10 (Q-10). The predominant fatty acids were C18 : 1ω7c, C17 : 1ω6c and summed feature 3 (C16 : 1ω7c and/or iso-C15 : 0 2-OH). The genomic DNA G+C content was 61.7 mol%. In the polar lipid profile, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, one unidentified phospholipid and one sphingoglycolipid were the major compounds; and another sphingoglycolipid was present in a minor amount. Based on the genotypic and phenotypic data, strain PQ-2(T) represents a novel species of the genus Croceicoccus , for which the name Croceicoccus naphthovorans sp. nov. is proposed. The type strain is PQ-2(T) ( =CGMCC 1.12805(T) =NBRC 110381(T)). In addition, emended descriptions for the genus Croceicoccus and the species C. marinus are given.


Influence of carbohydrate polymer shaping on organic dye adsorption by a metal-organic framework in water.
A number of studies have been conducted to develop new metal-organic frameworks (MOFs) as adsorbents for the removal of contaminants from polluted water. However, few reports exist describing detailed and thorough examinations of the effects of shaping on the adsorption properties of MOFs. In this study, a thorough analysis and comparison was conducted of the Orange II and Rhodamine B dye adsorption properties of unshaped MIL-100(Fe) (MIL) particles and alginate polymer-shaped MIL beads (MIL-alg). The adsorption affinities of Orange II and Rhodamine B for unshaped MIL were observed to be higher than those for shaped MIL-alg because partial coating of the surface of MIL particles by alginate polymer weakens adsorption forces. Kinetic analysis using a two-compartment model indicates that the contribution of the slow step in the mechanistic pathway for adsorption is more pronounced in MIL-alg compared to MIL because slow dye diffusion takes place in the alginate polymer. We believe that these fundamental findings will have a beneficial impact on approaches to design shaped MOFs that display improved dye removal performance.


Increased ion throughput using tristate ion-gate multiplexing.
For time dispersive ion mobility experiments detail control over the mechanism of ion beam modulation is necessary to establish optimum performance as this parameter greatly influences the temporal width of the ion beam arriving at the detector. When sampling continuous ion sources the temporal sampling or the incoming ion beam is often achieved by the electronic modulation of a grid or electric field. Not surprisingly, the rate at which a given ion population traverses this gating region is directly proportional to an ion's population and the applied electric field. This scenario establishes conditions where discrimination of the incoming ion beam may occur when the ion gate modulation rate is minimized. Recent developments in the mechanical construction of ion gates and their subsequent operation suggest that the mobility discrimination during ion gating may be minimized, however, it is remains unclear how this behavior will translate to ion beam multiplexing approaches. In this present work, we compare the performance levels of the tri-state ion shutter (3S-IS) to the two-state ion shutter (2S-IS) using a series of Fourier transform ion mobility mass spectrometry (FT-IMMS) experiments. The performance of the two different shutter operating principles were evaluated using ion multiplexing using tetraalkylammonium salts (TXA ions; T5-T8, T10, T12) bradykinin, and a set of reversed sequence isomeric pentapeptides using a variety of different ion gate frequency sweeps. Noticeable increases in ion throughput were observed for the 3S-IS with 95% and 45% increases in ion counts for the T5 and T12 ions respectively compared to the 2S-IS. Similarly, a 27% and 55% increase in ion counts was observed for the [M + 2H]2+ and [M + H]+ ions of bradykinin, respectively. In addition, a 10% increase in resolving power was also observed for the 3S-IS compared to the 2S-IS. Overall, utilization of the 3S-IS effectively minimizes both discrimination of slower ions and the impact of gate depletion effect common to traditional ion gating techniques.


A mechanistic investigation of the enhanced cleavage at histidine in the gas-phase dissociation of protonated peptides.
Enhanced gas-phase cleavage of peptides adjacent to histidine was investigated. The peptides examined were angiotensins III (RVYIHPF) and IV (VYIHPF) as well as synthetic peptide analogues with altered key residues ((R)VYI-X-Z-F; X = F or H and Z = A, P, or Sar) or a fixed charge M3P(+)CH(2)C(O)-VYIHPF. While all singly protonated peptide ions containing both histidine and arginine fragment nonselectively, the doubly protonated peptide ions with arginine and histidine, and the singly protonated peptides containing histidine but not arginine, cleave in a selective manner. In particular, dominant complementary b+/y+ product ions resulting from cleavage between the HP amide bond are observed. For the fixed-charge derivative, selective cleavage occurs only if a proton is added to produce a doubly charged precursor. The results are consistent with involvement of a protonated histidine in the selective cleavage. The ratio of b+/y+ is determined by the identity of the residue C-terminal to histidine and by the ability of protonated histidine to transfer a proton to the C-terminal leaving fragment. This was probed further by systematically changing the residue C-terminal to histidine and by alkylating histidine. The results indicate that while b+/y+ complementary ion pairs dominate in doubly protonated RVYIHPF, b5(2+) and b6(2+) product ions dominate the spectra of doubly protonated RVYIHAF. Also, dominant b5(2+) product ions are observed when the histidine side chain is alkylated (H) in doubly protonated RVYIHPF. Based on all of the results, a selective fragmentation mechanism for enhanced cleavage at histidine involving an atypical b ion structure is proposed.


Developmental differences in visual and auditory processing of complex sentences.
Children aged 8 through 11 (N = 250) were given a word-by-word sentence task in both the visual and auditory modes. The sentences included an object relative clause, a subject relative clause, or a conjoined verb phrase. Each sentence was followed by a true-false question, testing the subject of either the first or second verb. Participants were also given two memory span measures: digit span and reading span. High digit span children slowed down more at the transition from the main to the relative clause than did the low digit span children. The findings suggest the presence of a U-shaped learning pattern for on-line processing of restrictive relative clauses. Off-line accuracy scores showed different patterns for good comprehenders and poor comprehenders. Poor comprehenders answered the second verb questions at levels that were consistently below chance. Their answers were based on an incorrect local attachment strategy that treated the second noun as the subject of the second verb. For example, they often answered yes to the question "The girl chases the policeman" after the object relative sentence "The boy that the girl sees chases the policeman." Interestingly, low memory span poor comprehenders used the local attachment strategy less consistently than high memory span poor comprehenders, and all poor comprehenders used this strategy less consistently for harder than for easier sentences.


Renal morphology and function and urine electrolytes in experimental acute renal failure produced by cyclosporine and ischemia.
It has been difficult to produce a good animal model for cyclosporine nephrotoxicity. It has been suggested that by following 20 minutes of renal ischemia with four daily doses of cyclosporine 60 mg/kg intraperitoneally, one can create a model of reproducible renal failure. We observed excessive mortality (65%), due in part to cyclosporine's CNS effects, with these combined insults in the Munich Wistar rat. In contrast, cyclosporine alone in this dosage produced only 17% mortality and resulted in a similar degree of renal failure. Pair-fed and pair-watered vehicle and saline controls were used. The morphologic changes brought about by the castor oil vehicle of the parenteral cyclosporine solution were qualitatively similar to those brought about by cyclosporine by light microscopy, although the severity of the changes was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum also were seen in other groups. Urine sodium determined by flame photometry and urine chloride determined by Saltex reagent strips tended to be high in the initiation phase of cyclosporine-induced acute renal failure and low in the maintenance phase. In animals that developed acute renal failure following the combination of ischemia and cyclosporine, the initial urine sodium and chloride were significantly correlated with the eventual degree of renal failure. The use of Saltex urine chloride sticks in clinical urine samples showed that the readings correlated well with urine sodium and chloride determined by conventional methods, suggesting that these strips may be useful in making a quick diagnosis in the setting of acute renal failure.


HsaI: a restriction enzyme from human being.
The HsaI restriction enzyme from the embryos of human, Homo sapiens, has been isolated with both the tissue extract and nuclear extract. It proves to be an unusual enzyme, clearly related functionally to Type II endonuclease. HsaI seems to be an isoschizomer of EcoRI, but it has a distinctive property of elution, differing from EcoRI. Upon SDS-polyacrylamide gel electrophoresis, the enzyme preparation showed Coomassie blue staining bands, having the molecular weight of 65,000 and 22,000 daltons in size, respectively.


Piceatannol-Loaded Bilosome-Stabilized Zein Protein Exhibits Enhanced Cytostatic and Apoptotic Activities in Lung Cancer Cells.
Piceatannol (PIC) is a naturally occurring polyphenolic stilbene, and it has pleiotropic pharmacological properties. Moreover, PIC has cytotoxic actions among various cancer cells. In this work, preparations of PIC-loaded bilosome-zein (PIC-BZ) were designed, formulated, and characterized, and the optimized PIC-BZ cytotoxic activities, measured as half maximal inhibitory concentration (IC50), against lung cancer cell line was investigated. Box-Behnken design was utilized in order to examine the effect of preparation factors on drug entrapment and particle size. PIC-BZ showed a spherical shape after optimization, and its particle size was determined as 157.45 ± 1.62 nm. Moreover, the efficiency of drug entrapment was found as 93.14 ± 2.15%. The cytotoxic activity evaluation revealed that the adjusted formulation, which is PIC-BZ formula, showed a substantially smaller IC50 versus A549 cells. Cell cycle analysis showed accumulation of cells in the G2-M phase. Moreover, it showed in the sub-G1 phase, a rise of cell fraction suggestion apoptotic improving activity. Increased early and late phases of apoptosis were demonstrated by staining of cells with annexin V. Furthermore, the cellular caspase-3 protein expression was significantly raised by PIC-BZ. In addition, the wound healing experiment confirmed the results. To conclude, compared to pure PIC, PIC-BZ demonstrated a higher cell death-inducing activity against A549 cells.


Relation of biophysical response of coarcted aortic segment to balloon dilatation with development of recoarctation following balloon angioplasty of native coarctation.
To evaluate the role of biophysical response of the coarcted segment to balloon dilatation in the causation of aortic recoarctation. Tertiary care centre/university hospital. Retrospective case series. Records of 67 consecutive infants and children undergoing balloon angioplasty of native aortic coarctations were examined for an 8.7 year period ending September 1993. At 12 months (median) follow up catheterisation, 15 (25%) of 59 children developed recoarctation, defined as a gradient > 20 mm Hg. Stretch (balloon circumference--preballoon coarcted segment circumference/preballoon coarcted segment circumference), gain (postballoon coarcted segment circumference--preballoon coarcted segment circumference), and recoil (balloon circumference--postballoon coarcted segment circumference) were calculated from measurements obtained from cineangiograms performed before and immediately after balloon dilatation. The stretch in 44 children without recoarctation (2.18 (1.23)) was similar (p > 0.1) to that in 15 children with recoarctation (1.90 (0.65)), implying that similar balloon dilating stretch was applied in both groups. Greater gain (p < 0.05) was observed in the group without recoarctation (8.8 (8.0) mm) than in the recoarctation group (5.7 (2.7) mm) but this was not substantiated in the infant population. However, the recoil was greater (p < 0.001) in the group without recoarctation (5.1 (4.3) mm) than in the recoarctation group (2.1 (1.1) mm); this was also true in the infant group. Greater recoil in the patients without recoarctation implies preservation of intact elastic tissue in the coarcted segment. In the recoarctation group, with less recoil, the elastic properties may not have been preserved, thereby causing recoarctation. There might be a more severe degree of cystic medial necrosis in the recoarctation group than in the no recoarctation group. This needs confirmation in future studies.


Structural Analysis of Monoclonal Antibodies with Top-down and Middle-down Electron Transfer Dissociation Mass Spectrometry: The First Decade.
Monoclonal antibodies (mAbs) are protein biotherapeutics with a proven efficacy toward fighting life-threatening diseases. Their exceptional healing potential drives the annual increase in the number of novel mAbs and other antibody-like molecules entering clinical trials and the number of approved mAb-based drugs. Mass spectrometry (MS) offers high selectivity and specificity for the potentially unambiguous identification and comprehensive structural characterization of proteins, including at the proteoform level. It is thus not surprising that MS-based approaches are playing a central role in the biopharma laboratories, complementing and advancing traditional biotherapeutics characterization workflows. A combination of MS approaches is required to comprehensively characterize mAbs' structures: the commonly employed bottom-up MS approaches are efficiently complemented with mass measurements at the intact and subunit (middle-up) levels, together with product ion analysis following gas-phase fragmentation of precursor ions performed at the intact (top-down) and subunit (middle-down) levels. Here we overview our group's contribution to increasing the efficiency of these approaches and the development of the novel strategies over the past decade. Our particular focus has been on the top-down and middle-down MS methods that utilize electron transfer dissociation (ETD) for gas-phase protein ion fragmentation. Several approaches pioneered by our group, particularly an ETD-based middle-down approach, constitute a part of commercial software solutions for the mAb's characterization workflows.


Cough and Asthma.
Cough is the most common complaint for which patients seek medical attention. Cough variant asthma (CVA) is a form of asthma, which presents solely with cough. CVA is one of the most common causes of chronic cough. More importantly, 30 to 40% of adult patients with CVA, unless adequately treated, may progress to classic asthma. CVA shares a number of pathophysiological features with classic asthma such as atopy, airway hyper-responsiveness, eosinophilic airway inflammation and various features of airway remodeling. Inhaled corticosteroids remain the most important form of treatment of CVA as they improve cough and reduce the risk of progression to classic asthma most likely through their prevention of airway remodeling and chronic airflow obstruction.


Inter-laboratory validation of a harmonized PNH flow cytometry assay.
A network comprising 11 laboratories aimed to consolidate PNH testing by developing and validating an assay guided by previous guidelines and studies. Network analyses of >20 native samples yielded key findings that were used to create and reshape the final protocol. Twenty-seven native samples were distributed to all participating laboratories for blind testing, local analysis, and subsequent re-analysis by a central laboratory. Inter-laboratory clone size precision (coefficient of variation [CV]) was monitored for each sample, and the findings used to refine the test protocol. Linearity and precision tests were performed, assay limits of blank and detection were calculated, and limits of quantification were determined. When using the final protocol, enumeration of cells with a PNH phenotype by all participating laboratories was comparable, with no clinically significant discrepancies or false-positive or false-negative results reported. Of note, the biological characteristics of the sample affected precision. For example, CVs were higher when PNH and normal cells showed contiguous expression of GPI-linked antigens. A red cell gating strategy that eliminated non-specific type II PNH phenotypic events was devised, enabling reliable reporting of events in the type II red cell gate. The final protocol provided an assay with a Limit of Quantification of 0.01% for neutrophils and red cells, and 0.1% for monocytes. We describe a robust network-validated PNH assay that may aid other laboratories to set up and validate high resolution PNH analysis. © 2018 International Clinical Cytometry Society.


Hepatitis-B Vaccine Response in Inflammatory Bowel Disease Patients: A Systematic Review and Meta-analysis.
Data on efficacy of hepatitis-B vaccine (HBV) in patients with inflammatory bowel disease (IBD) is limited. Our aim was to review the literature and perform meta-analysis of available studies to quantify efficacy of HBV in patients with IBD. We conducted a comprehensive search of several databases (inception to July 2020) to identify studies evaluating efficacy of HBV in patients with IBD. Random effects model was used to calculate the pooled rates and I2 percentage values were used to assess the heterogeneity. A total of 14 studies (2375 patients) were included. Four data sets were available from 2 studies that compared HBV response in patients with IBD against healthy controls. The pooled odds ratio of HBV response in IBD patients was 0.13 (95% CI, 0.05-0.33, P = 0.001). The pooled proportion of adequate immune response (AIR) was 64% (95% CI, 55-72.1, P = 0.003) from 13 data sets, and effective immune response (EIR) was 39.7% (95% CI, 30.7-49.5, P = 0.04) from 10 data sets. Patients with IBD on immunosuppression demonstrated significantly reduced HBV response as compared with general population.


Role of oxygen functional groups in reduced graphene oxide for lubrication.
Functionalized and fully characterized graphene-based lubricant additives are potential 2D materials for energy-efficient tribological applications in machine elements, especially at macroscopic contacts. Two different reduced graphene oxide (rGO) derivatives, terminated by hydroxyl and epoxy-hydroxyl groups, were prepared and blended with two different molecular weights of polyethylene glycol (PEG) for tribological investigation. Epoxy-hydroxyl-terminated rGO dispersed in PEG showed significantly smaller values of the friction coefficient. In this condition, PEG chains intercalate between the functionalized graphene sheets, and shear can take place between the PEG and rGO sheets. However, the friction coefficient was unaffected when hydroxyl-terminated rGO was coupled with PEG. This can be explained by the strong coupling between graphene sheets through hydroxyl units, causing the interaction of PEG with the rGO to be non- effective for lubrication. On the other hand, antiwear properties of hydroxyl-terminated rGO were significantly enhanced compared to epoxy-hydroxyl functionalized rGO due to the integrity of graphene sheet clusters.


Portraits of science. "The most versatile physicist of his generation".
P. M. S. Blackett (1897-1974) entered Cambridge University and the Cavendish Laboratory as a young veteran of the first world war. His innovative research with the Wilson cloud chamber resulted in photographic evidence of nuclear transformation and the existence of the positron. In the 1950s and 1960s, he helped to pioneer the use of paleomagnetic evidence in support of the theory of continental drift. A leader of operational research during the second world war, Blackett became an outspoken critic in the postwar period of American atomic policy and British development of nuclear weapons, taking on a public role for which he was sometimes criticized.


Metal-directed assembly of chiral bis-Zn(II) Schiff base structures.
Tetra-Schiff bases derived from (chiral) bis-salphen ligand scaffolds furnish, upon metalation with appropriate metal reagents, their multinuclear structures with associated Zn(OAc)(2) or Zn(OH)(2) fragments. The tendency of retaining these salts was investigated using four different (chiral) bis-salphen scaffolds. The presence of the additional Zn ions was supported by NMR studies, mass determinations and X-ray crystallography showing in two cases the possible mode of coordination within these multinuclear structures. In one case, dimerization of the Zn(3) complex leads to a unique hexanuclear Zn(6) complex being a mixture of diastereoisomeric complexes as revealed by NMR spectroscopy.


Early intestinal growth and development in poultry.
While there are many accepted "facts" within the field of poultry science that are in truth still open for discussion, there is little debate with respect to the tremendous genetic progress that has been made with commercial broilers and turkeys (Havenstein et al., 2003, 2007). When one considers the changes in carcass development in poultry meat strains, these genetic "improvements" have not always been accompanied by correlated changes in other physiological systems and this can predispose some birds to developmental anomalies (i.e. ascites; Pavlidis et al., 2007; Wideman et al., 2013). Over the last decade, there has been increased interest in intestinal growth/health as poultry nutritionists have attempted to adopt new approaches to deal with the broader changes in the overall nutrition landscape. This landscape includes not only the aforementioned genetic changes but also a raft of governmental policies that have focused attention on the environment (phosphorus and nitrogen excretion), consumer pressure on the use of antibiotics, and renewable biofuels with its consequent effects on ingredient costs. Intestinal morphology has become a common research tool for assessing nutritional effects on the intestine but it is only one metric among many that can be used and histological results can often be interpreted in a variety of ways. This study will address the broader body of research on intestinal growth and development in commercial poultry and will attempt to integrate the topics of the intestinal: microbial interface and the role of the intestine as an immune tissue under the broad umbrella of intestinal physiology.